12/28/2011

1

TB Intensive San Antonio, Texas

November 29-­December 2, 2011

TB Disease: ATS/CDC/IDSA Treatment Guidelines

Barbara Seaworth, MD, FIDSA, FACP November 30, 2011

Barbara Seaworth, MD, FIDSA, FACP has the following disclosures to make:

Is on the HHSC advisory committee for the Elimination of Tuberculosis and receives research funding from Otsuka Pharmaceuticals. No other relevant financial relationships with any commercial companies pertaining to this educational activity

12/28/2011

2

Treatment of Tuberculosis

Barbara J Seaworth MD

Medical Director Heartland National TB Center

Objectives

Identify standard regimens for treatment of drug susceptible TB Discuss strategies resulting in improved patient outcomes

Intensity of dosing Prolongation of therapy

Recognize those at risk of poor outcomes Manage a TB suspect

12/28/2011

3

Purpose 1 5. Recommended Treatment Regimens 36

1 CONTENTS OF 6. Practical Aspects of Treatment 42

Summary 1 THE 80-Page 7. Drug Interactions 45

1. Introduction and Background 13 Document 8. Treatment in Special Situations 50

2. Organization and Supervision of Treatment 15 9. Management of Relapse, Treatment Failure, and Drug Resistance

66

3. Drugs in Current Use 19 10. Treatment of Tuberculosis in Low-Income Countries: Recommendations and Guidelines of the WHO and the IUATLD

72

4. Principles of Antituberculosis Chemotherapy 32 11. Research Agenda for Tuberculosis Treatment 74

USPHS/IDSA Evidenced-based Rating Scale

Strength of the Recommendation A = Preferred B = Acceptable alternative C = Offer when unable to give A or B D = Should generally NOT be offered E = Should NEVER be offered

Quality of Supporting Evidence I = Randomized clinical trial II = Clinical trial, not randomized III = Expert opinion

12/28/2011

4

Strategies Stressed in Guidelines

Identification of patients at increased risk of relapse Obtain sputum smear and culture at end of initial phase of treatment (2months)

Extended therapy for patients with drug-susceptible pulmonary TB

Who have cavitation on initial CXR and

Who have a positive sputum culture at 2 months

Counting Doses Define treatment completion by number of doses taken as well as duration of treatment

Strategies Stressed in Guidelines

RIFABUTIN (RBT): May be used as a primary drug for patients (especially HIV+) receiving medications having unacceptable interactions with rifampin (e.g. Protease Inhibitors, methadone)

Fluoroquinolones (Levofloxacin or Moxifloxacin) may be used when first line drugs are not tolerated or the organism is resistant

12/28/2011

5

Treatment of Culture-Positive Drug Susceptible Pulmonary TB

General conclusions from the literature 6 mo (26 wk) is the MINIMUM duration of RX 6 mo regimens require rifampin and INH throughout and PZA for the first 2 months 6 9 mo regimens are effective without INH if PZA given throughout Intermittent regimens (2-3x/wk): DOT ONLY!

Drug susceptible isolate

Treatment of Culture-Positive Drug Susceptible Pulmonary TB

General conclusions from the literature: Without PZA - minimum duration is 9 months Without rifampin - minimum duration is 12 months (up to 18 months) Streptomycin and ethambutol (EMB) are approximately equivalent in effect

Because of high incidence of Streptomycin resistance ethambutol is preferred for initial therapy

Use streptomycin only if isolate is proven susceptible

12/28/2011

6

Treatment Regimens for TB Disease

Initiation phase of therapy 8 weeks INH, Rifampin and PZA +/-EMB

Continuation phase of therapy 16 weeks INH and Rifampin

Treatment of Culture Positive Pulmonary Tuberculosis

Regimens Rated A-1 (HIV Uninfected) INITIAL PHASE 2 mo I,R,Z,E daily (56 doses, 8wks) or 2 mo I,R,Z,E 5x/wk (40 doses, 8wks) then CONTINUATION PHASE -4 mo - I,R daily (126 doses, 18 wks) or -4 mo I,R 5x/wk (90 doses, 18 wks) or -4 mo I,R, 2x/wk (36 doses, 18 wks)

12/28/2011

7

Treatment of Culture Positive Pulmonary Tuberculosis

Regimens Rated A-II (HIV Uninfected)

2weeks I,R,Z,E daily (14 doses) then 6 weeks I,R,Z,E twice weekly (12 doses)

PLUS (DOT only) -4mo I,R Twice weekly (36 doses, 18 weeks) or

continuation phase

Initial phase

Treatment of Culture Positive Pulmonary Tuberculosis

Regimens Rated A-III (HIV Uninfected)

2 weeks I,R,Z,E 5x/week (10 doses) then 6 weeks I,R,Z,E twice weekly (12 doses)

PLUS (DOT only)

-4mo I,R Twice weekly (36 doses, 18 weeks) or

continuation phase

Initial phase

12/28/2011

8

Treatment of Culture Positive Pulmonary TB

THRICE WEEKLY » Regimen Rated BI (HIV uninfected)

Initial phase 2mo I,R,Z,E 3x/week (24 doses, 8weeks)

PLUS

Continuation phase 4mo I,R 3x/wk (54 doses, 18 weeks)

Nucleic Acid Amplification NAAT FDA cleared for respiratory specimens

M.tb Direct Test® (MDT) (Gen-Probe®) also referred to as PCR tests

DNA probe detects M TB complex RNA directly in the sputum

>95% sensitive for AFB smear + TB 55 75% of AFB smear (culture +) patients detected

Does not distinguish live and dead bacilli

12/28/2011

9

CDC Recommendations for NAAT

NAAT should be performed on at least one

respiratory specimen from each patient with signs and symptoms of pulmonary TB for whom a diagnosis of TB is being considered but has not yet been established, and for whom the test result would alter case management or TB

Why Use A NAAT ? Confirms AFB + case as M TB

If AFB + case is NAAT negative on 2 specimens

Suspect this is not M TB Suspend Contact investigation and Hold TB treatment unless TB strongly suspected.

If patient is not strongly suspected as M TB and is NAAT negative x 2,

Remove from isolation.

12/28/2011

10

Case Management

Monthly clinical visit check response to therapy, evaluate for toxicity:

hepatitis, visual acuity, Ishihara Plates

repeat education (document!)

Monthly laboratory to check liver enzymes, CBC Document susceptibility of isolate prior to stopping ethambutol

Pt educated regarding: signs/symptoms of visual and liver toxicity & need to report these to provider

Case Management

For pulmonary TB Monthly sputum until two consecutive cultures are negative

-2 month sputum is crucial

80% should convert by 2 months, 95% by 3 months

12/28/2011

11

Drug Susceptibility Tests

INH, Rifampin, Ethambutol, and PZA are recommended for each initial isolate Expect results by day 28

If the private lab does not do susceptibilities, referral may lead to unnecessary delays

Positive culture should be sent for DST within 24 hrs, lab should not wait for culture to grow on solid media

Specimen received in the lab

Day

At 24 hours, expect smear

results

0 1

At 48 hours, expect results of NAAT or

Molecular DST

2 21 28 42-56 3

At 72 hours, expect results of

IGRA

When should I consider my specimen delayed?

At 21 days, expect a culture ID

(TB or not)

At 28 days, expect 1st line

susceptibility results, expect 2nd line 4 weeks

after requested

At 6-8 weeks, expect the culture to be

finalized if negative

12/28/2011

12

When Should You Expect the Culture to Turn Positive? Time to Culture Positive by Presence of Cavitary Lesions

Perrin Int J TB Lung Dis, Dec 2010

When Should You Expect the Culture to Turn Positive? Time to Culture Positive by Presence of Cavitary Lesions

Perrin Int J TB Lung Dis, Dec 2010

12/28/2011

13

What About Ethambutol?

A four drug regimen is recommended until susceptibility tests are reported If treatment is being initiated after drug susceptibility tests are known and the organisms are susceptible, ethambutol is not necessary if patient is given both INH and rifampin Ethambutol can be stopped as soon as the lab reports an isolate susceptible to INH & rifampin.

TBTC STUDY 22: RATE OF FAILURE or RELAPSE, BY REGIMEN, SPUTUM CULTURE,

AND CHEST RADIOGRAPH

0

5

10

15

20

25

Culture + Culture - Cavitary Non-Cavitary

23.5

5.6

14.4

2.9

16.7

3.8

8.9

2.5

Rate of Failure/Relapse (%)

HP1 HR2

Positive Negative Cavitary Non-Cavitary

culture at 2 mo Chest radiograph at study entry Lancet 2002; 360:528.

20%  

Rate  of  Failure/Relapse  

16.7%   3.8%   8.9%   2.5%  

12/28/2011

14

Prolongation of Continuation Phase

Continuation phase increased to 7 mo if initial

CXR is cavitary & culture is positive at 2 mo Rational for Extending Therapy

Continuation of PZA for an additional 2 months was not helpful in drug susceptible disease Prolongation of continuation phase by 2 months decreased relapses in silico-tuberculosis from 20% to 2%

Effect of Prolonging Therapy on Treatment Failure or Relapse

Treatment of Silico-tuberculosis

Outcome SHRZ - 6mo* SHRZ 8mo* (n=49) (n=50) ____________________________________ Relapse 20% 2% * Three times weekly therapy Am Rev Respir Dis 1991;143:262-267

12/28/2011

15

End of Therapy (EOT) Cavity: A Risk Factor for Relapse

Hamilton; Int J Tuber Lung Dis 2008

Independent of culture results

New Treatment Guidelines Tailoring Treatment Regimens

Prolongation of continuation phase Positive 2 month culture with cavitary disease Extrapulmonary disease

Meningitis Disseminated disease in children

HIV TB in children and adolescents

ATS, CDC, IDSA: Treatment of Tuberculosis 2003

12/28/2011

16

Additional New Treatment Guidelines Tailoring Treatment Regimens

Consider - Prolongation of continuation phase when patient:

Slow to clinically or radiographically respond Positive 2 month culture OR cavitary disease? End of therapy (EOT) cavity present

<10% ideal body weight?

Relapse

Circumstance in which a patient becomes and remains culture-negative while receiving antituberculosis drugs but at some point after completion of therapy, either becomes culture-positive again or experiences clinical and radiographic deterioration consistent with active tuberculosis

do it right this time!

12/28/2011

17

Treatment Guidelines 2003

Confirm relapse bacteriologically Use DNA fingerprinting to identify new infection causing the disease versus relapse Identify drug susceptibility pattern of isolate

Relapsed Tuberculosis

Most relapses occur within the first 6 12 months after stopping therapy but some occur 5 or more years later Nearly all drug susceptible patients who were treated with a rifamycin and received DOT will relapse with drug susceptible organisms

Treat with standard RIPE regimen

12/28/2011

18

Relapsed Tuberculosis Management Strategies

If culture & susceptibility studies (those treated in other countries ) were not done but treatment given by DOT

Usual treatment with RIPE

Watch carefully for clinical deterioration - Consider expanding the regimen by adding at least 2 drugs

Consider an expanded regimen if immune suppressed, significantly ill, or extensive disease

Relapsed Tuberculosis Management Strategies

Suspect drug resistance if

Patients treated with self administered therapy Patient was poorly adherent Patient deteriorates clinically or radiographically during initial weeks of treatment

Consider expanded regimen, especially if immune suppressed

RIPE plus a fluoroquinolone and an injectable

12/28/2011

19

Patients at Risk of Relapse

Who Should We Suspect? What Can We Do Differently to Decrease the Risk?

Treatment Related Risk Factors for Early Relapse of TB

Evaluation of 113 cases of relapsed TB when matched with case controls

Non-cavitary TB, relapse rate: 1.1% Cavitary TB relapse rates:

Thrice weekly Rx: 7.8% Daily Rx: 3.3% Extended thrice weekly: 0.5% Extended daily 0.4%

Either intensive phase or both was beneficial

» Chang, Am J Respir Crit Care Med. 2004; 170: 1124-30

12/28/2011

20

Treatment Related Risk Factors for Early Relapse-Dosing Intensity

Review of trials, 200 cases of relapse, 6 month Rx

Relapse rates higher when intermittent therapy used especially in initiation phase

Daily IP, 3 x/wk CP: 1.6% Daily IP 2x/wk CP: 2.8% 3/wk IP and CP: 5.0%

Relapse higher especially with cavitary disease and positive 2 month cultures

Only 6 month daily or 6 month daily IP and 3/wk CP had relapse rates <5%

Chang Am J Respir Crit Care Med 2006; Vol 174 p 1153

In the Treatment of TB,

requires more treatment, and the fewer total doses, the higher the risk

What should we conclude? First: More treatment means more cures

Second: Programs need to consider some individualization of therapy

Third: Should not deter us from intermittent therapy but should remind us of need for sophisticated management based on case-specific circumstances

Should not be surprised that individuals differ in their response.

» Vernon & Iademarco (CDC) Am J Resp Crit Care Med 2004: 170, pp 1040-41

12/28/2011

21

Medical Factors Associated With Relapse-Dosing Intensity

Cavitary TB Extensive disease on CXR; bilateral infiltrates Positive 2 month culture Associated medical conditions

Diabetes HIV Malabsorption of TB drugs

Tuberculous lymphadenitis Underweight at diagnosis and failure to gain Drug resistant disease Prior treatment for tuberculosis

Treatment Factors Associated with Relapse of Tuberculosis

DOT Adherence Dosing intensity (Dose itself) Duration of therapy

Intensive phase Continuation phase Both

Rifampin containing regimen

12/28/2011

22

Length of Treatment and Relapse Risk

Johnson; AJRCCM June 09

HIV neg, 2 mo culture neg, Non-Cavitary TB in Uganda.

Risk of Relapse With a Four Month Treatment Regimen

Treatment of TB and Optimal Dosing Schedules

Kwok Chiu Chang, Chi Chiu Leung,

Jacques Grosset, Wing Wai Yew Thorax December, 2010

Systematic Review of 17 analytic studies 9 systematic reviews, 8 controlled studies and 2 case-control studies.

Levels of evidence and grades of recommendations assigned according to clinical evidence with reference to Scottish Intercollegiate Guidelines

12/28/2011

23

Non HIV related TB (11 studies)

Suggests that intermittent Rx reduces TB treatment efficacy as shown by a higher risk of relapse or failure

Negative impact most prominent in presence of cavities

Review suggests with standard 6 mo Rx - no significant difference between daily throughout & daily in initial phase

Level of evidence: 1+

Avoid intermittent doses, especially in initial phase and in presence of cavities

TB With INH Resistance (2 studies)

Suggests that dosing intermittency reduces TB treatment efficacy as shown by:

Higher risk of treatment failure, relapse or acquired drug resistance

Level of evidence 1+

Avoid dosing intermittency, especially in the initial phase in the presence of INH resistance

12/28/2011

24

HIV related TB ( 3 studies)

Suggests intermittent Rx, especially in initial phase reduces treatment efficacy as shown by

a higher risk of treatment failure, relapse, or acquired Rifampin resistance

Level of evidence 1+

Avoid intermittency, especially in the initial phase in HIV TB

Why is the Initial Phase of Therapy So Important?

12/28/2011

25

Importance of the Initiation Phase

Evidence suggests Effect of dosing schedules on treatment efficacy is best harnessed in the initial phase

Evidence has existed in vitro for several decades that:

the more rapid the anti-bacterial effect the less likely is the emergence of persisters and the lower is the risk of relapse.

Importance of Rifampin Especially in the Initiation Phase

Rifampin is the only first line TB drug with putative activity against persisters Persisting bacilli are the source of relapses

12/28/2011

26

Populations of Mycobacteria INH Rifampin EMB

Rifampin PZA

Rifampin

Importance of the Initiation Phase

Rifampin is the only first line TB drug with putative activity against persisters Persisters may revert back and forth to other subpopulations of bacilli

Optimizing bactericidal and sterilizing activity early will minimize overall bacterial load present during continuation phase

12/28/2011

27

Relapsed Tuberculosis - Case Study

Case Study

47 yr old male, recurrence of TB Weight at Diagnosis 117 pounds (<10% IBW) Two months, 114 pounds Three months, 114 pounds Four months, 115 pounds

Extensive cavitary disease on CXR Sputum smear + 5 ½ months Sputum culture + 3 ½ months

What is problem?

12/28/2011

28

Lack of Weight Gain and Relapse Risk, TBTC Study 22

Relapse risk high in those underweight at diagnosis 19.1% versus 4.8%

after 2 months of treatment: Relapse risk 18.4% vs. 10.3% If also cavitary disease: 18.9% If cavitary and + 2 month culture: 50.5%

» Khan. 2006 Am J Resp & Crit Care Med;174:344-48

Nutrition Risk Score (NRS): Relation to Respiratory Failure & Death

Miliary TB (MTB) develops in 1 2% of patients and is associated with acute respiratory failure (ARF) and death NRS failure (ARF) and death

Lower BMI, fewer lymphocytes, lower cholesterol, & albumin in those who died 14/56 (25%) patients with Miliary TB developed ARF

Kim, Europ Resp Society 2008

12/28/2011

29

Treatment in Special Situations

Active TB During Pregnancy Diagnosis may be difficult

Respiratory symptoms common in late pregnancy Reluctance to do a CXR Extra-pulmonary disease is even more difficult

Outcomes for BOTH mom and baby are improved with treatment during pregnancy

Infection control is important at time of delivery if mom is still infectious

12/28/2011

30

Active TB During Pregnancy

Treatment: INH, Rifampin, Ethambutol x 9 months

Stop ethambutol if susceptible to INH and rifampin PZA only if drug resistance is present

PZA regarded as safe by most countries in world

Follow carefully for hepatotoxicity- risk is increased During pregnancy Three months postpartum

Delayed Response Culture Positive at 3 Months

TB lab should automatically repeat susceptibility studies on last positive culture check to be sure Assess adherence

Consider serum drug levels Evaluate response to therapy

Clinically and radiographically By the time you know this it is 4 months into therapy!

12/28/2011

31

Culture Positive at 4 Months

Repeat susceptibility studies On last positive culture

Serum drug levels if not previously done Clinical evaluation

Augment therapy Add at least two and preferably three new drugs to which the isolate is likely to be susceptible Even if no clinical or radiographic evidence of failure

MMWR Treatment of Tuberculosis 2003; 52

Tuberculosis Drug Serum Level Monitoring Recommended

Delayed response to therapy Advanced AIDS with evidence of malabsorption Seriously ill patient to maximize therapy ? Diabetics Toxicity evaluation Use of second line drugs Acquired drug resistance Relapse Potential for drug-drug interactions Renal and hepatic insufficiency

12/28/2011

32

Management of TST + Persons With an Abnormal CXR

Isolated CXR with nodules and/or fibrotic lesions:

If no symptoms - wait Collect sputum culture Evaluate for symptoms Repeat CXR

If CXR stable at 2 3 months and cultures are negative, treat as LTBI

Isolated CXR with nodules and/or fibrotic lesions:

If patient has any signs or symptoms of TB disease: the patient is a TB suspect

Start 4 drugs

Never start a single drug in a patient with possible active TB

Culture Negative TB TB suspect with positive TST or IGRA

Risk factors for TB Abnormal CXR Usually clinical symptoms

All cultures are negative

Classify based on clinical and/or radiograph response to treatment at 2 months

Clinical or CXR improvement Culture Negative TB Treat for 4 months (children and HIV + 6 months) RIPE for 2 months, then RIE +/- PZA dependent on INH resistance

12/28/2011

33

Why Do Doctors Give Patients Moxifloxacin for a Lower Respiratory Illness?

LRTIs: A Leading Cause of Disease Burden Globally: All Ages, 2004

In 2006, pneumonia was the leading cause of death from infectious disease in the United States

From Reuters Health Information: Moxifloxacin Improves Outcomes in Hospitalized Pneumonia Patients

Ott, Europ Resp J , Sept 2011

W.C. 12-18-01

Prolonged Positive Smears

51 year old male Slow clinical and CXR improvement Prolonged conversion of cultures (10 weeks) Prolonged conversion of smears (7½ months)

12/28/2011

34

Significance of Persistent + AFB Smears

Review of lab data of 428 patients, 30 with smear persistently + >20weeks

23/30 had a negative culture

Of those with negative cultures - none relapsed Most received standard therapy for 12 months

PZA was continued for 2-3 months

» Al-Moamary Chest 1999; 116:726-731

W. C. 12-11-2002

Prolonged Positive Smears

12 months of RX Culture and smear 20 months after stopping TB meds CXR still extensive cavitary infiltrates

12/28/2011

35

Mycobacterium bovis A member of the M TB complex which is what is identified by all TB labs or PCR

Similar to other members but is resistant to PZA

Is associated with extra pulmonary disease and increased mortality

Is common in children (> 1 year) along U.S. Mexico border

Non-pasturized milk and cheese a food borne disease as well as respiratory

M bovis & Genotyping - Texas

1

3 2

0 1

5

8

10

0%

20%

40%

60%

80%

100%

0

2

4

6

8

10

12

2000 2001 2002 2003 2004 2005 2006 2007

year

# of bovis cases

% of TB genotyped

All M. bovis are resistant to PZA and need treatment for 9 months with INH and Rifampin +/- EMB

12/28/2011

36

Management of Treatment Interruptions

Initial phase of therapy <14 days complete standard # of doses

>14 days restart from the beginning

Continuation phase

>80% doses by DOT if initial smear , may stop

< 80% doses by DOT and/or initial smear + Repeat culture

Management based on clinical and bacteriological factors.

TB Research

Impact on Future TB Treatment

12/28/2011

37

Rifampin Dose - High is Better

Higher peak serum concentrations were linked to

Improved killing of MTB, Suppression of resistance Post antibiotic effect

Short half life not important but peak concentration was

Gumbo; Antimicrob Agents Chemother, 2007

TB Trial Consortium Study 29

Part I compare standard therapy (rifampin 10mg/kg) to: 3 x/wk rifapentine 15mg/kg + Moxi/PZA/EMB Daily rifampin 15mg/kg + Moxi/PZA/EMB Daily rifapentine 7.5mg/kg + Moxi/PZA/EMB

Part II Increase to rifapentine 20mg/kg 3x/wk, Daily rifampin 20mg/kg Rifapentine 10mg/kg

12/28/2011

38

TBTC Study 27 Moxifloxin Substituted for Ethambutol

Burman; Am J Resp Crit Care Med 2006

Where to Get More Information

HEARTLAND NATIONAL TB CENTER 1-800-TEX LUNG: Medical Consultation and Technical Assistance Line Future training courses

CDC TB Educate TBresources.com